Five interrelated projects supported by three cores to improve the understanding of pathophysiology in osteoporosis by elucidating the cellular, molecular, and genetic mechanisms that underlie loss of bone, and by examining the role of osteocytes in preserving bone integrity and strength. The central theme remains that loss of bone in the adult skeleton is mainly the result of disordered control of cell number, specifically that too many osteoclasts exist relative to the need created by bone resorption. Extensions of these themes are that the importance of deficient cell number applies also to the osteocyte, and that for all three bone cell types cell death as is important as cell birth in determining overall cell numbers. Molecular and cellular biology approaches, gene mapping, and generation of transgenic and knockout mice will be used to test the projects' interrelated hypotheses. O'Brien's project will further explore the molecular links between osteoclastogenesis and osteoblastogenesis during normal bone remodeling and clarify the mechanism of coupling of bone resorption. Manolagas's project will attempt to unravel the molecular mechanisms for the separate effects of estrogen deficiency on cell production and on cell lifespan; it will also seek an explanation for the paradox of the bone protective efficiency of estrogen in males in androgen in females. Jilka's project will focus on the importance of osteoblast progenitor cell proliferation and apoptosis, and further study Jilka's project will focus on the importance of osteoblast progenitor cell proliferation and apoptosis, and further study the inverse relationship between adipogenesis and osteoblastogenesis in aging bone marrow. Reis's project will narrow the search for the molecular genetic basis of osteopenia in the SAMP6 mouse, and use the results to extend genetic studies to human subjects. Bellido's project will elucidate the signals that control osteocyte viability in response to both pharmacological agents and mechanical forces. In addition to the management, administration, and statistics Core which will support interactions between research projects, the Animal Research Core and the Bone morphometry and Molecular Imaging Core will each provide crucial services supporting several projects in a cost effective and scientifically advantageous manner.